Title

Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases.

Journal

The Journal of neuroscience : the official journal of the Society for Neuroscience

Volume

31

Issue

None

Pages

9858-68

Date

2011-07-06

Authors

Patterson KR | Binder LI | Song Y | Pigino GF | LaPointe NE | Andreadis A | Fu Y | Morfini GA | Brady ST | Kanaan NM

Again, coperfusion of the PAD peptide with either I-2 (50 nM) (Fig. 5A) or ING-135 (100 nM) (Fig. 5B) anterograde FAT inhibition.

As observed with 􏰁2–18 tau aggregates (LaPointe et al., 2009), monomeric 􏰁2–18 6D tau showed no effect on FAT (Fig. 4 A, D), demonstrating that PAD is necessary for 6D tau- mediated inhibition of anterograde FAT.

The PAD peptide selectively in- hibited anterograde FAT (Fig. 4 B, D), but not retrograde FAT (Fig. 4B,E).

Collectively, these data indicate that PAD is both necessary and sufficient to inhibit an- terograde FAT by activating the PP1–GSK3 cascade.

P-c-Jun was dephosphorylated to a greater extent in PAD peptide-perfused axoplasms than their scrambled peptide- perfused counterpart (Fig. 5F ), suggesting that the PAD peptide induced activation of endogenous axoplasmic phosphatases.

A trend of elevated GSK3 activity (􏰈32%) relative to PKC activity ( p 􏰄 0.28, paired t test; n 􏰄 3) was observed for axoplasms incubated with the PAD peptide (mean 􏰄 4.9 􏰉 2.5), compared with those incubated with scram- bled peptide (mean 􏰄 3.7 􏰉 1.7), which supports the results from vesicle motility assays.

To evaluate the relevance of these find- ings in human disease, we generated a novel monoclonal antibody, termed TNT1, which specifically recognizes PAD.

These data indicated that increased PAD exposure, as revealed by TNT1 immunoreac- tivity, occurs early in AD and remains present throughout the disease process.

Together, these data suggest that increased PAD exposure represents an early event in AD pathogenesis and that AT8 may not be required for PAD ex- posure in situ.

perfusion of full-length WT tau monomers (2 􏰊M) (Fig. 1 A) had no effect on FAT in squid axoplasm (Fig. 2 A), while 6D and 6P tau monomers (2 􏰊M) significantly inhibited anterograde FAT when compared with WT tau monomer (Fig. 2 B, C) or buf- fer controls (data not shown).

Together, these data demonstrate that, as posited for aggregated tau (LaPointe et al., 2009), short N-terminal isoforms of tau inhibit anterograde FAT by a mech- anism involving activation of PP1 and GSK3 that is independent of microtubule binding.

Neither 6D nor 6P tau (Fig. 2D) had an effect on retrograde FAT

Soluble AT8 tau monomers inhibited anterograde FAT (Fig. 6 A, C), while retrograde trans- port was unaffected (Fig. 6 A, D). These data indicate that phos- phorylation of tau at the AT8 epitope, which is associated with hyperphosphorylation of tau in AD and other tauopathies, renders soluble monomeric tau capable of inhibiting antero- grade FAT.

Consistent with our model, 􏰁144 –273 tau monomers significantly inhibited antero- grade FAT (Fig. 6 B, C), while retrograde FAT remained unaf- fected (Fig. 6 B, D).Together, these data indicate that disease- associated modifications and mutations in tau that increase exposure of PAD promote activation of the PP1–GSK3 pathway and inhibition of anterograde FAT.

Filamentous, but not soluble, forms of wild-type tau inhibit anterograde, kinesin-based fast axonal transport (FAT) by activating axonal protein phosphatase 1 (PP1) and glycogen synthase kinase 3 (GSK3), independent of microtubule binding. Amino acids 2-18 of tau, comprising a phosphatase-activating domain (PAD), are necessary and sufficient for activation of this pathway. Various pathogenic forms of tau displaying increased exposure of PAD inhibited anterograde FAT in squid axoplasm. Immunohistochemical studies using a novel PAD-specific monoclonal antibody in human postmortem tissue indicated that increased PAD exposure represents an early pathogenic event in AD that closely associates in time with AT8 immunoreactivity. We propose a model of pathogenesis in which disease-associated changes in tau conformation lead to increased exposure of PAD, activation of PP1-GSK3, and inhibition of FAT

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